| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Platinum Sensitive Recurrent High Grade Serous Ovarian/Primary Peritoneal or Fallopian tube Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. Assess the biological effects in the primary tumor following a short pre-operative course of treatment with Olaparib in patients with platinum sensitive relapsed ovarian cancer; the biological effects are assess in terms of the degree of PAR or PARP-1 inhibition.
2. Evaluate germline HRD mutations and tissue mutation with respect to BRCA1/2, RAD51B, RAD51C, RAD51D, PPM1D, FANCM, BRIP1, PALB2 and BARD1.
3. Generate initial clinical efficacy data for future studies. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
1. Assess the safety and tolerability of pre-operative Olaparib.
2. Assess the response rate to olaparib in the neoadjuvant period.
3. Assess PFS and PFS2 with olaparib in comparison to platinum based chemotherapy.
4. Assess the value of ctDNA as a prognostic factor alone and in comparison to CA125.
5. Evaluate gene expression change in tumour tissue before and after treatment with Olaparib.
6. Assess secondary mutation rate in surgical tumour specimens following PARP therapy and at progression.
7. Evaluate changes in blood based biomarkers using ctDNA before, during and after treatment with Olaparib in an attempt to correlate with gene expression changes, BRCA mutation status and histopathological changes.
Exploratory Objectives:
1. Assess for mechanisms of resistance with a focus on reverse BRCA mutations, non-homologous end-joining and RAD 51 levels.
2. Assess mutational spectra and correlation with outcome.
3. Evaluate variations in allele frequency of BRCA1/ |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The sub-study and corresponding objectives are embedded within the larger therapeutic study. There is no separate protocol for the sub-study.
Objectives:
- Assess the biological effects in the primary tumor following a short pre-operative course of treatment with Olaparib in patients with platinum sensitive relapsed ovarian cancer; the biological effects are assess in terms of the degree of PAR or PARP-1 inhibition.
- Evaluate germline HRD mutations and tissue mutation with respect to BRCA1/2, RAD51B, RAD51C, RAD51D, PPM1D, FANCM, BRIP1, PALB2 and BARD1
- Assess the value of ctDNA as a prognostic factor alone and in comparison to CA125
- Evaluate gene expression change in tumour tissue before and after treatment with Olaparib
- Assess secondary mutation rate in surgical tumour specimens following PARP therapy and at progression.
- Evaluate changes in blood based biomarkers using ctDNA before, during and after treatment with Olaparib in an attempt to correlate with gene expression changes, BRCA mutation status and histopathological changes.
- Assess for mechanisms of resistance with a focus on reverse BRCA mutations, non-homologous end-joining and RAD 51 levels
- Assess mutational spectra and correlation with outcome
- Evaluate variations in allele frequency of BRCA1/2 across the surgical specimen as a marker of heterogeneity and correlate this with clinical response
- Determine if additional mutations found were detectable on ctDNA as a viable alternative to biopsy
- Perform shallow sequencing to assess for tumor heterogeneity on the surgical specimen
|
|
| E.3 | Principal inclusion criteria |
1. Histologically proven recurrent high grade serous ovarian/primary peritoneal or fallopian tube cancer.
2. Patients must have disease amenable to pre-operative biopsy.
3. Patients must have disease deemed suitable for surgical debulking.
4. Patients must have had at least one line of platinum based therapy, with a progression free interval of at least 6 months.
5. Patients must have shown platinum sensitivity to their last line of platinum therapy.
6. Age ≥18 years.
7. ECOG performance status 0-1 within 7 days of registration.
8. Life expectancy of greater than 3 months.
9. Patients must have normal organ and marrow function as defined below within 7 days of registration:
Hemoglobin ≥100 g/L
Absolute neutrophil count ≥1.5 x 109/L
Platelets ≥100 x 109/L
Total bilirubin ≤1.5x ULN
AST(SGOT) ≤2.5x ULN
ALT(SGPT) ≤2.5x ULN
Creatinine ≤1.5x ULN
OR
Creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
10. Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.
11. Ability to understand and the willingness to sign a written informed consent document.
12. Subject’s willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. |
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| E.4 | Principal exclusion criteria |
1. History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib.
2. History of allergic reactions attributed to platinum precluding further use.
3. Radiation therapy within 4 weeks of registration.
4. Use of any other systemic, targeted, immunotherapy, chemotherapy, or investigational agents within 4 weeks of registration.
5. Previously received a PARP inhibitor [prior use of Iniparib is allowed].
6. Other malignancy within the last 2 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, Grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥2 years. Patients with a history of localized breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than two years prior to registration, and that the patient remains free of recurrent or metastatic disease.
7. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
8. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. Recent bowel obstruction is a contraindication to enrolment.
9. Concomitant use of known potent CYP3A4 inhibitors such as but not limited to ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
10. Concomitant use of known potent CYP3A4 inducers such as but not limited to; phenytoin, rifampicin, rifapentin, rifabutin, carbamazepine, phenobarbital, nevirapine, modafinil, St. John’s Wort (Hypericum perforatum)
11. No other anti-cancer therapy including immunotherapy, hormonal therapy, biological therapy, other novel agents or investigational agents is to be permitted
12. Persistent toxicities (CTCAE v 4.03 grade >2) caused by previous cancer therapy, excluding alopecia.
13. Patients with myelodysplastic syndrome/acute myeloid leukaemia.
14. Patients with known brain metastases.
15. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
16. Patients with known active hepatitis (i.e., hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids.
17. Pregnant or breastfeeding women are excluded.
18. Receipt of live attenuated vaccine within 30 days prior to enrollment.
19. Patients with > Grade 2 hearing impairment as per CTCAE v 4.03.
20. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| There is no information on variation of PAR or PARP-1inhibition level available for the proposed patient population; therefore this study is designed to have sufficient power to detect a small to medium reduction of PAR or PARP-1inhibition level after 4-8 weeks treatment from the baseline level, which is measured as a Cohen’s D (standardised mean difference) ≥0.3 (small reduction from baseline) or ≥ 0.5 (medium reduction from baseline) in the sample size estimation. With a significance level of 0.05 (one-sided), and 80% power, 27 patients with paired measurements are required to detect a medium reduction (Cohen’s D =0.5) and 71 patients with paired measurements are required to detect a small reduction (Cohen’s’D=0.3). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The end of the study is defined as the date when the last patient, last visit (LPLV) occurs. Hereafter all endpoints will be evaluated following data cleaning and a data lock. |
|
| E.5.2 | Secondary end point(s) |
Secondary end-points are exploratory in nature and will be hypothesis generating.
This study aims to generate initial clinical efficacy data comparing chemotherapy with olaparib monotherapy for future studies. This will be achieved by the randomisation part of study design. With 25-35 patients randomised to each of the two arms, it will provide a sufficient degree of precision to estimate variance of a clinical efficacy endpoint.
If there is suggestion of clinical efficacy based on this initial cohort consideration will be made to expand the patient population.
Any deviation from the original statistical plan will be described in the final report.
All reasonable attempts will be made to minimize the amount of missing data, although it is recognized that some missing data is inevitable. Wherever possible, the reason for missing data will be captured and reported, however, no interpolation of missing data will be performed for any outcome.
|
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The end of the study is defined as the date when the last patient, last visit (LPLV) occurs. Hereafter all endpoints will be evaluated following data cleaning and a data lock. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| France |
| Italy |
| New Zealand |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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